Venlafaxine, (±) 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol, is a nontricyclic compound which has been described for use in treatment of depression, general anxiety disorders, and vasomotor symptoms.
Venlafaxine and the acid addition salts thereof are described in U.S. Pat. No. 4,535,186. These compounds have been studied extensively and described in, for example, U.S. Pat. No. 4,761,501 and Pento, J. T. Drugs of the Future 13(9):839-840 (1988).
The hydrochloride salt of venlafaxine is currently commercially available in the United States under the trade name Effexor®. Effexor®, which is a racemic mixture of the (+) and (−) enantiomers of venlafaxine, is indicated for the treatment of depression. This drug is typically administered orally to adults in compressed tablet form taken two or three times a day within the range 75 to 350 mg/day.
EP 0639374 describes the use of venlafaxine in the treatment of obesity, panic disorder, post-traumatic stress disorder, late luteal phase dysphoric disorder, attention deficit disorder, Gilles de la Tourette syndrome, bulimia nervosa, generalized anxiety disorder or Shy Drager syndrome. EP-A-654264 teaches the use of venlafaxine in treating incontinence. U.S. Pat. No. 5,506,270 (Upton et al.) claims venlafaxine's use in methods of treating hypothalamic amenorrhea in non-depressed women. U.S. Pat. No. 5,530,013 (Husbands et al.) claims venlafaxine's use for enhancing cognition.
Vasomotor symptoms (VMS), referred to as hot flushes and night sweats, are the most common symptoms associated with menopause, occurring in 60% to 80% of all women following natural or surgically-induced menopause. Such symptoms have also been described in patients undergoing chemotherapy, e.g. for breast cancer. Venlafaxine has been described for the treatment of VMS in e.g. US Published Patent Application No. 2005 01435979, and the documents cited therein.
Syntheses of venlafaxine and other 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine analogs have been described, for example, in JP Yardley, et al., J Med Chem, 1990, 33, 2899-2905.
Additional useful 2-phenyl-2-(1-hydroxycycloalkyl)ethylamines have been described, for example, in US20050143394.
What are needed are alternative methods and intermediates useful for the synthesis of venlafaxine compounds.